1. Field of the Invention
The present invention relates to a class of nitric oxide (NO) releasing metal complexes characterised by the presence of a coordinated piperazineNONOate residue, and their use as pharmacological agents able to induce vascular relaxation, to exert an endothelio-protective effect on the coronary district, and to stimulate re-endothelialization and angiogenesis processes.
The invention also relates to a process for preparing the aforesaid compounds.
The invention further relates to pharmaceutical formulations containing one or more of the aforesaid compounds.
2. Description of the Background
The pharmacological activity of the compounds of the invention has been evaluated by their relaxation induction effect in vascular preparations (rabbit aorta rings) precontracted with noradrenaline (Amerini et al., J. Cardiovasc. Pharmacol., 28: 82-88, 1966). The endothelio-protective and pro-angiogenetic effects of the compounds have also been evaluated in a study on the proliferation and migration of endothelial cells of the microcirculatory system (M. Ziche et al., J. Clin. Invest. 94: 2036-2044, 1994).
Nitric oxide performs an important role in a variety of biological and physiological processes as a vasodilator, neurotransmitter and bioregulator, and is involved in the defensive immune system (Nitric Oxide: Principles and Action, J. Lancaster Jr. ed., Academic Press, San Diego, Calif. 1996). It is produced in the body enzymatically from the amino acid L-arginine by means of NO synthase (R. Iyengar, D. J. Stuehr and M. A. Marietta, Proc. Natl. Acad. Sci. USA 84, 6369, 1987), which is present in various isoforms. The action of the nitric oxide depends on its capacity to activate the enzyme guanylate cyclase and to induce in this manner the production of cyclic GMP. The constituent isoform of the NO synthase is present mainly at the endothelial level and is responsible for controlling the vasal tone. Another type of NO synthase, which is induced in activated macrophages and in other cells, synthesizes NO as a cyclotoxic agent against tumoral cells and micro-organisms.
Inadequate NO production determines numerous pathological conditions, for which this molecule has to be administered from the outside. However, given that this is a radical molecule of relatively short life, it is not administered as such but via precursors. These include the classical nitrovasodilators such as nitroglycerin, sodium nitroprussiate, isoamyl nitrite and pentaerythritol tetranitrate, which have been used for some time but give rise to various problems in controlling the rate and extent of NO release and in producing side effects. The availability of molecules able to release physiologically more suitable NO concentrations with lesser side effects would therefore be of important therapeutic advantage.